Small molecule phagocytosis inhibitors for immune cytopenias

Neschadim, Anton; Kotra, Lakshmi P.; Branch, Donald R.

doi:10.1016/j.autrev.2016.06.004

Cited by 9 publications

(9 citation statements)

References 50 publications

(49 reference statements)

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“…3–5 Cytotoxic effects of T cells have also been described. 6 Phagocytosis of antibody-decorated platelets via Fc-receptors or, following complement activation, via complement receptors were long-accepted concepts for the understanding of platelet destruction. 6,7 Recent studies have pro vided some evidence that autoantibodies may also trigger more complex processes, such as platelet activation, platelet desialylation, or platelet apoptosis, all of which could lead to Fc-independent platelet clearance.…”

Section: Introductionmentioning

confidence: 99%

“…6 Phagocytosis of antibody-decorated platelets via Fc-receptors or, following complement activation, via complement receptors were long-accepted concepts for the understanding of platelet destruction. 6,7 Recent studies have pro vided some evidence that autoantibodies may also trigger more complex processes, such as platelet activation, platelet desialylation, or platelet apoptosis, all of which could lead to Fc-independent platelet clearance. 8–11 More recently, there has also been evidence that the glycoprotein specificity of the autoantibodies could be important; for example, in a study by Li et al ., 10 desialylation occurred in the presence of anti-GPIbα, but not in the presence of anti-GP IIb/IIIa antibodies.…”

Section: Introductionmentioning

confidence: 99%

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Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia

et al. 2019

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Platelet autoantibody-induced platelet clearance represents a major pathomechanism in immune thrombocytopenia (ITP). There is growing evidence for clinical differences between anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib/IX mediated ITP. Glycoprotein V is a well characterized target antigen in Varicella-associated and drug-induced thrombocytopenia. We conducted a systematic study assessing the prevalence and functional capacity of autoantibodies against glycoprotein V. A total of 1140 patients were included. In one-third of patients, platelet-bound autoantibodies against glycoproteins Ib/IX, IIb/IIIa, or V were detected in a monoclonal antibody immobilization of platelet antigen assay; platelet-bound autoantiglycoprotein V was present in the majority of samples (222 out of 343, 64.7%). Investigation of patient sera revealed the presence of free autoantibodies against glycoprotein V in 13.5% of these patients by an indirect monoclonal antibody immobilization of platelet antigen assay, but in 39.6% by surface plasmon resonance technology. These antibodies showed significantly lower avidity (association/dissociation ratio 0.32±0.13 vs . 0.73±0.14; P <0.001). High- and low-avidity antibodies induced comparable amounts of platelet uptake in a phagocytosis assay using CD14 + positively-selected human macrophages [mean phagocytic index, 6.81 (range, 4.75-9.86) vs . 6.01 (range, 5.00-6.98); P =0.954]. In a NOD/SCID mouse model, IgG prepared from both types of anti-glycoprotein V autoantibodies eliminated human platelets with no detectable difference between the groups from the murine circulation [mean platelet survival at 300 minutes, 40% (range, 27-55) vs . 35% (16-46); P =0.025]. Our data establish glycoprotein V as a relevant immune target in immune thrombocytopenia. We would suggest that further studies including glycoprotein V will be required before ITP treatment can be tailored according to platelet autoantibody specificity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia

et al. 2019

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“…It has been suggested that platelet destruction mainly results from phagocytosis, and that inhibition of phagocytosis may prevent the loss of platelets . Now therefore, it is suggested that small molecule inhibitors for phagocytosis could be developed as first‐in‐class drugs to combat the increased platelet destruction that occurs in ITP …”

Section: Methodsmentioning

confidence: 99%

“…5 Now therefore, it is suggested that small molecule inhibitors for phagocytosis could be developed as first-inclass drugs to combat the increased platelet destruction that occurs in ITP. 6 With regard to discover small molecules that regulate phagocytosis, we have recently reported biarylamide compounds, including MPS03, inhibit macrophage phagocytosis of zymosan ( Figure 1). 7,8 In addition, we demonstrated that the biarylamides reduce the expression level of Rac1, Rac2, and Cdc42, which are the key regulators of phagocytosis.…”

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confidence: 99%

Synthesis and Biological Evaluation of Biarylamide Derivatives as Inhibitors of Phagocytosis in Macrophages

Kang

Song

Hyun

et al. 2016

Bulletin Korean Chem Soc

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“…Indeed, the MMA can not only serve as a functional assay to address discrepancies between serology and biology, it has also been used to retrospectively investigate the cause of hemolysis after intravenous immunoglobulin (IVIG) therapy 17 . It has also been used to examine the structure-function of chemical inhibitors of FcγR-mediated phagocytosis [18][19][20] and to study the downstream signaling of FcγR-mediated phagocytosis 21 . In our laboratory, in addition to using a human MMA, we are developing a murine MMA using primary mouse peripheral blood mononuclear cells (PBMCs) and autologous RBCs.…”

Section: Introductionmentioning

confidence: 99%

Use of a Monocyte Monolayer Assay to Evaluate Fcγ Receptor-mediated Phagocytosis

Tong¹,

Branch

2017

JoVE

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Although originally developed for predicting transfusion outcomes of serologically incompatible blood, the monocyte monolayer assay (MMA) is a highly versatile in vitro assay that can be modified to examine different aspects of antibody and Fcγ receptor (FcγR)-mediated phagocytosis in both research and clinical settings. The assay utilizes adherent monocytes from peripheral blood mononuclear cells isolated from mammalian whole blood. MMA has been described for use in both human and murine investigations. These monocytes express FcγRs (e.g., FcγRI, FcγRIIA, FcγRIIB, and FcγRIIIA) that are involved in immune responses. The MMA exploits the mechanism of FcγR-mediated interactions, phagocytosis in particular, where antibody-sensitized red blood cells (RBCs) adhere to and/or activate FcγRs and are subsequently phagocytosed by the monocytes. In vivo, primarily tissue macrophages found in the spleen and liver carry out FcγR-mediated phagocytosis of antibody-opsonized RBCs, causing extravascular hemolysis. By evaluating the level of phagocytosis using the MMA, different aspects of the in vivo FcγR-mediated process can be investigated. Some applications of the MMA include predicting the clinical relevance of allo-or autoantibodies in a transfusion setting, assessing candidate drugs that promote or inhibit phagocytosis, and combining the assay with fluorescent microscopy or traditional Western immunoblotting to investigate the downstream signaling effects of FcγR-engaging drugs or antibodies. Some limitations include the laboriousness of this technique, which takes a full day from start to finish, and the requirement of research ethics approval in order to work with mammalian blood. However, with diligence and adequate training, the MMA results can be obtained within a 24-h turnover time.

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Small molecule phagocytosis inhibitors for immune cytopenias

Cited by 9 publications

References 50 publications

Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia

Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia

Synthesis and Biological Evaluation of Biarylamide Derivatives as Inhibitors of Phagocytosis in Macrophages

Use of a Monocyte Monolayer Assay to Evaluate Fcγ Receptor-mediated Phagocytosis

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Small molecule phagocytosis inhibitors for immune cytopenias

Cited by 9 publications

References 50 publications

Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia

Glycoprotein V is a relevant immune target in patients with immune thrombocytopenia

Synthesis and Biological Evaluation of Biarylamide Derivatives as Inhibitors of Phagocytosis in Macrophages

Use of a Monocyte Monolayer Assay to Evaluate Fc&#947; Receptor-mediated Phagocytosis

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Use of a Monocyte Monolayer Assay to Evaluate Fcγ Receptor-mediated Phagocytosis